TY - JOUR
T1 - Stimulation of cholesterol biosynthesis in mitochondrial complex I-deficiency lowers reductive stress and improves motor function and survival in mice
AU - Schirris, Tom J.J.
AU - Rossell, Sergio
AU - de Haas, Ria
AU - Frambach, Sanne J.C.M.
AU - Hoogstraten, Charlotte A.
AU - Renkema, Herma
AU - Beyrath, Julien D.
AU - Willems, Peter H.G.M.
AU - Huynen, Martijn A.
AU - Smeitink, Jan A.M.
AU - Russel, Frans G.M.
AU - Notebaart, Richard A.
PY - 2021/4/1
Y1 - 2021/4/1
N2 - The majority of cellular energy is produced by the mitochondrial oxidative phosphorylation (OXPHOS) system. Failure of the first OXPHOS enzyme complex, NADH:ubiquinone oxidoreductase or complex I (CI), is associated with multiple signs and symptoms presenting at variable ages of onset. There is no approved drug treatment yet to slow or reverse the progression of CI-deficient disorders. Here, we present a comprehensive human metabolic network model of genetically characterized CI-deficient patient-derived fibroblasts. Model calculations predicted that increased cholesterol production, export, and utilization can counterbalance the surplus of reducing equivalents in patient-derived fibroblasts, as these pathways consume considerable amounts of NAD(P)H. We show that fibrates attenuated increased NAD(P)H levels and improved CI-deficient fibroblast growth by stimulating the production of cholesterol via enhancement of its cellular efflux. In CI-deficient (Ndufs4−/−) mice, fibrate treatment resulted in prolonged survival and improved motor function, which was accompanied by an increased cholesterol efflux from peritoneal macrophages. Our results shine a new light on the use of compensatory biological pathways in mitochondrial dysfunction, which may lead to novel therapeutic interventions for mitochondrial diseases for which currently no cure exists.
AB - The majority of cellular energy is produced by the mitochondrial oxidative phosphorylation (OXPHOS) system. Failure of the first OXPHOS enzyme complex, NADH:ubiquinone oxidoreductase or complex I (CI), is associated with multiple signs and symptoms presenting at variable ages of onset. There is no approved drug treatment yet to slow or reverse the progression of CI-deficient disorders. Here, we present a comprehensive human metabolic network model of genetically characterized CI-deficient patient-derived fibroblasts. Model calculations predicted that increased cholesterol production, export, and utilization can counterbalance the surplus of reducing equivalents in patient-derived fibroblasts, as these pathways consume considerable amounts of NAD(P)H. We show that fibrates attenuated increased NAD(P)H levels and improved CI-deficient fibroblast growth by stimulating the production of cholesterol via enhancement of its cellular efflux. In CI-deficient (Ndufs4−/−) mice, fibrate treatment resulted in prolonged survival and improved motor function, which was accompanied by an increased cholesterol efflux from peritoneal macrophages. Our results shine a new light on the use of compensatory biological pathways in mitochondrial dysfunction, which may lead to novel therapeutic interventions for mitochondrial diseases for which currently no cure exists.
KW - Cholesterol biosynthesis
KW - Complex I deficiency
KW - Leigh syndrome
KW - Metabolic network modeling
KW - NAD(P)H
KW - Ndufs4 mice
U2 - 10.1016/j.bbadis.2020.166062
DO - 10.1016/j.bbadis.2020.166062
M3 - Article
C2 - 33385517
AN - SCOPUS:85099256584
VL - 1867
JO - Biochimica et Biophysica Acta. Molecular Basis of Disease
JF - Biochimica et Biophysica Acta. Molecular Basis of Disease
SN - 0925-4439
IS - 4
M1 - 166062
ER -